Allergic and asthmatic reactions pose serious public health problems worldwide. Pollen allergy alone (allergic rhinitis or hay fever) affects about 10-15% of the population, and generates huge economic costs. For example, reports estimate that pollen allergy generated $1.8 billion of direct and indirect expenses in the United States in 1990 (Fact Sheet, National Institute of Allergy and Infectious Diseases, www.niaid.nih.gov/factsheets/allergystat.html; McMenamin, Annals of Allergy 73:35, 1994; incorporated herein by reference). More serious than the economic costs associated with pollen and other inhaled allergens (e.g., molds, dust mites, animal danders) is the risk of anaphylactic reaction observed with allergens such as food allergens, insect venoms, drugs, and latex.
Allergic reactions occur when an individual""s immune system overreacts, or reacts inappropriately, to an encountered antigen. No allergic reaction is thought to occur the first time an individual is exposed to a particular antigen. However, the initial immune response to an antigen primes the system for subsequent allergic reactions. In particular, the antigen is taken up by antigen presenting cells (e.g., macrophages or dendritic cells) that degrade the antigen and then display antigen fragments to T cells. The activated T cells respond by secreting a collection of cytokines that affect other cells of the immune system. The profile of cytokines secreted by responding T cells determines whether subsequent exposures to the particular antigen will induce allergic reactions. When T cells respond by secreting interleukin-4 (IL-4), the effect is to stimulate the maturation of B cells that produce IgE antibodies specific for the antigen. These antigen-specific IgE antibodies then attach to specific receptors on the surface of mast cells and basophils, where they act as a trigger to initiate a rapid reaction to subsequent exposures to the antigen.
When the individual next encounters the antigen, it is quickly bound by these surface-associated IgE molecules. Each antigen typically has more than one IgE binding site, so that the surface-bound IgE molecules quickly become crosslinked to one another through their simultaneous (direct or indirect) associations with antigen. Such cross-linking induces mast cell degranulation, resulting in the release of histamines and other substances that induce the symptoms associated with allergic reaction. Individuals with high levels of IgE antibodies are known to be particularly prone to allergies.
Allergic asthma is a chronic, IgE-mediated lung disease characterized by inflammation and airway hyperresponsiveness (AHR). Asthma is a major public health problem in the United States; nearly 17 million Americans suffer from this often debilitating disease. Moreover, asthma morbidity and mortality have been rising over the last two decades. The prevalence rate increased by 75% from 1980 to 1994, and despite the increased use of medications, deaths from asthma rose 58%.
Clinically, asthma is expressed as episodic breathlessness, wheezing, chest tightness, and cough (U.S. Centers for Disease Control. Morbidity and Mortality 47:1022, 1998; incorporated herein by reference). The airways of asthmatic subjects are characterized by chronic inflammation with infiltration of the bronchial mucosa by lymphocytes, eosinophils, and mast cells together with epithelial desquamation, goblet cell hyperplasia, and thickening of the submucosa (Steering Committee for International Study of Asthma and Allergies in Childhood, Lancet 351:1225, 1998; Kay J. Allergy Clin. Immunol. 87:893, 1991; each of which is incorporated herein by reference).
Numerous studies have demonstrated that Th2-type cytokines, such as IL-4, IL-5, and IL-13, produced by activated CD4+ T cells, play a central role in the pathogenesis of allergic asthma (see, for example, Lemanske et al., in Allergy: Principles and Practice. C. V. Mosby, Co., St. Louis, Mo., pg. 320, 1993; Mosmann et al., J. Immunol. 136:2348, 1986; Mosmann et al., Annu. Rev. Immunol. 7:145, 1989; Walker et al., Am. Rev. Respir. Dis. 146:109, 1992; Robinson et al., N. Engl. J. Med. 326:298, 1992; Finkleman et al., J. Immunol. 141:2335, 1988; Schleimer et al., J. Immunol. 148:1086, 1992; Hamaguchi et al., J. Exp. Med. 165:268, 1987; Campbell et al., Proc. Natl. Acad. Sci. USA 84:6629, 1987; Zurawski et al., Immunol. Today 15:19, 1994; each of which is incorporated herein by reference).
Atopic human subjects, when exposed to the relevant asthmatic antigen, suffer an acute IgE-dependent response, often followed by a late-phase inflammatory response 6-12 hours later (Beasley et al., Am. Rev. Respir. Dis. 139:806, 1989; Metzger et al., Clin. Rev. Allergy 3:145, 1985; each of whichlis incorporated herein by reference). The early (immediate) phase response is associated with mast cell degranulation and release of mediators such as histamine, tryptase, leukotrienes, and platelet-activating factor (Busse et al., Agents Actions Suppl. 28:41, 1989; Lemanske et al., in Allergy: Principles and Practice. C. V. Mosby, Co., St. Louis, Mo., pg. 320, 1993; each of which is incorporated herein by reference); the late phase response is associated with the infiltration of inflammatory cells, predominantly eosinophils, which release eosinophil major basic protein and other mediators that damage the epithelium and induce bronchoconstriction (Beasley et al., Am. Rev. Respir. Dis. 139:806, 1989; Busse et al., Agents Actions Suppl. 28:41, 1989; each of which is incorporated herein by reference).
As the significance of inflammation has become recognized in the pathogenesis of airway hyperresponsiveness, efforts have been made to treat asthma by reducing the inflammatory process. Corticosteroids are the most potent known non-specific anti-inflammatory agents and have been found to produce notable improvement in objective lung function of asthmatics. In view of the substantial side effects associated with systemic corticosteroids, inhaled corticosteroids are currently the first line of treatment. Inhaled steroids can be effective in decreasing inflammation and bronchoconstriction in patients, but the lack of specificity of their effects can also have negative results. Although the most frequently reported side effects of inhaled corticosteroids are local, systemic effects have also been reported. Thinning of the skin, bruising, adrenal suppression, decreased bone metabolism, and decreased growth (Barnes, N. Engl. J. Med. 332:868, 1995; incorporated herein by reference) are of particular concern, especially among children, in whom asthma appears to be rapidly increasing in frequency.
One approach to treating allergies is antigen immunotherapy, which attempts to xe2x80x9cvaccinatexe2x80x9d a sensitive individual against a particular allergen by periodically injecting or treating the individual with a crude suspension of the raw allergen. The goal is to modulate the allergic response mounted in the individual through controlled administration of known amounts of antigen. If the therapy is successful, the individual""s allergic response is diminished, or can even disappear. However, the therapy can require several rounds of vaccination, over an extended time period (3-5 years), and very often does not produce the desired results. Moreover, certain individuals suffer anaphylactic reactions to the vaccines, despite their intentional, controlled administration.
Another commonly used approach to treating allergic symptoms is the administration of histamine antagonists. These drugs are widely available in over-the-counter formulations, but unfortunately they merely mask the symptoms of the allergic response rather than providing any type of permanent cure or protection against recurrence.
Efforts are underway to develop more specific treatments for allergy and asthma (see, for example, Fahy et al., Am. J. Respir. Crit. Care Med. 155:1828, 1997; Boulet et al., Am. J. Respir. Crit. Care Med. 155:1835, 1997; Kung et al., Am. J. Respir. Cell Mol. Bio. 12:360, 1995; Mauser et al., Am. J. Respir. Crit. Care Med. 152:467, 1995; Holgate et al., J. Allergy Clin. Immunol. 98:1, 1996; each of which is incorporated herein by reference). Also, non-traditional treatments for these maladies are being explored. However, there remains a need for the development of improved allergy and asthma therapies, and particularly therapies to reduce the risk of anaphylaxis.
The invention provides improved treatments for allergies and asthma. In particular, the invention provides herbal formulation compositions that, when administered to an individual suffering from asthmatic or allergic symptoms, reduce the severity, intensity, and/or duration of at least some of those symptoms. Inventive compositions preferably reverse established allergic or asthmatic reactions to particular antigens. Alternatively or additionally, inventive compositions may prevent or delay an allergic or asthmatic reaction and/or may block or reduce the development of allergic or asthmatic sensitivity to antigens.
In one preferred embodiment, an inventive composition comprises one or more components of Fructus Pruni Mume (Wu Mei), Pericarpium Zanthoxyli Bungeanum (Chuan Jiao), Herba cum Radice Asari (Xi Xin), Rhizoma Coptidis (Huang Lian), Cortex Phellodendri (Huang bai), Rhizoma Zingiberis Officinalis (Gan Jiang), Radix Lateralis Aconiti Carmichaeli Praeparata (Fu Zi), Ramulus Cinnamomi Cassiae (Gui Zhi), Radix Ginseng (Ren Shen), and Radix Angelicae Sinensis (Dong gui). Other preferred compositions additionally comprise one or more components of Ganoderma lucidum (Ling Zhi). In a particularly preferred embodiment, the composition comprises the Chinese herbal remedy Wu Mei Wan (WMW) plus Ganoderma lucidum (Ling Zhi, LZ).
In another preferred embodiment, the composition comprises one or more components of Perillae frutescens (su zi), Descurainia Sophia (ting li zi), Raphanus sativus L. (lai fu zi), Marus alba L. (sang bai pi), Prunus armeniaca (xing ren), Scutellaria baicalensis (huang qin), Glycyrrhiza uralensis (gan cao), Ziziphus jujuba (da zao), Aster tataricus (zi wan), Pteria margaritaferae (zhen zhu mu), and Aussilago farfara (kuan dong hua).
In yet another preferred embodiment, the composition comprises one or more components of Perillae frutescens (su zi), Descurainia Sophia (ting li zi), Prunus armeniaca (xing ren), Scutellaria baicalensis (huang qing), Sophora flavescens (ku sen), Angesica sinensis (don gui), Paeonia lactiflora (bai shao), Peuraria lobata (ge gen), Platycodon grandiflorum (jie gen), Pteria margaritaferae (zhen zhu mu), Ganoderma lucidum (ling zhi), Glycyrrhiza uralensis (gan cao), Ziziphus jujuba (da zao), and Frash zingiber officinal (sheng jiang).
In certain preferred embodiments of the invention, inventive compositions are administered in combination with one or more standard therapies. For example, inventive compositions may be administered in combination with corticosteroids (e.g., inhaled, injected, or orally delivered corticosteroids), anti-histamines, decongestants, cromolyn sodium, standard immunotherapy, rush immunotherapy, etc. used to treat allergic or asthmatic symptoms.
Inventive compositions may optionally be characterized in one or more animal model systems.
Furthermore, the present invention provides a method of formulating an herbal remedy of the present invention, and/or of identifying active ingredients in inventive herbal compositions. For example, one or more active components of the herbs of the inventive compositions may optionally be extracted or purified using any technologies known in the art including, but not limited to chromatography, aqueous extraction, organic solvent extraction, etc. The active component and/or whole herbs may be combined with other pharmaceutically acceptable excipients or carriers to make pharmaceutical compositions.
The present invention also provides methods of treating allergies or asthma and/or preventing the development of allergies or asthma. The compositions of the present invention may be administered to an individual to prevent the development of, or reduce symptoms of, an allergic or asthmatic response to an allergen. For example, the inventive compositions may be administered substantially simultaneously with a known allergen in order to alter the immune response so that an allergic or asthmatic response does not develop, or develops to a lesser extent than would be observed in the absence of the inventive composition. In another preferred embodiment, the inventive composition is administered before exposure to a known allergen in order to lessen the allergic or asthmatic reaction. In yet another embodiment, the inventive composition is administered after exposure to a known allergen or after development of sensitization to the allergen in order to lessen the effect of potential allergic or asthmatic reactions in the future.
The present invention also provides methods of identifying and characterizing herbal remedies useful in the treatment of allergic reactions and asthma. In a preferred embodiment, an inventive test herbal remedy is administered to an animal model known to have an immune response similar to that of the individual to be treated with the herbal remedy. The herbal remedy may be administered at any time including, but not limited to, prior to sensitization, during sensitization, after sensitization, prior to challenge, during challenge, or after challenge. In a particularly preferred embodiment, the animal model used is the allergic mouse model. In vitro assays may also be used in characterizing herbal remedies. In a particularly preferred embodiment, a basophil histamine release assay is used in assessing herbal remedies.
In another aspect, the present invention provides methods of identifying herbs useful in preparing herbal remedies and methods of identifying active components of these herbs. Herbs or mixture of herbs are administered to animal models of allergic disease or are used in in vitro assays known to predict effects in vivo. In a preferred embodiment, the active components of the herbs or mixture of herbs are purified or partially purified. Various methods of purification and preparation may be used in providing the formulations to be studied. The prepared/purified formulations may be also used in the various in vitro and in vivo assays described in the present patent application to identify those herbs and active components responsible for treating or preventing allergic disease.